Transcriptional Role of the Cdk8 Kinase Module with Protein Synthesis Machinery Before and After Nitrogen Starvation

Abstract

Translation is tightly coupled to growth status. Efficient protein synthesis is necessary for cell growth in nutrient rich environments, while global translation inhibition combined with selective translation of stress‐responsive mRNAs helps limit growth in times of stress. How does the cell alter protein synthesis machinery to survive in stress such as nutrient deprivation? A few mechanisms in nitrogen starvation include selective degradation of specific mRNA‐binding translation factors, inhibition of activators of genes whose products are required for general translation, and the primarily cap‐independent selective translation of mRNAs necessary for the stress response. How and when these occur, however, have remained elusive. Here, we demonstrate in Saccharomyces cerevisiae that the highly conserved Cdk8 kinase module (CKM) of the mediator complex (cyclin C, Cdk8, Med13, and Med12) transcriptionally upregulates genes encoding 60S ribosome proteins and cap‐dependent initiation factors such as eIF4G1 in physiological conditions. Yeast CKM is known to predominantly repress stress response genes (SRG), and our previous findings revealed that SRG suppression is relieved through the degradation of Med13 and cyclin C following both cell survival and death cues. Our recent data suggest that degradation of the CKM following nitrogen starvation may play a transcriptional role in altering the levels of proteins no longer needed for general translation. Additionally, while cyclin C has a secondary role of promoting mitochondrial fragmentation in the cytoplasm following oxidative stress, we have previously found that Med13 goes to the cytoplasm to be degraded via autophagy following nitrogen starvation. Our preliminary data also shows Med13 associating with proteins involved in translation regulation in nitrogen starvation, suggesting it may also have a more direct role in controlling translation. The CKM is thus a multi‐faceted hub that can provide insight to how the cell adapts to stress on both the level of transcription and translation.